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Sex Difference of Egfr Expression and Molecular Pathway in the Liver

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Sex Difference of Egfr Expression and Molecular Pathway in the Liver Journal of Cancer 2016, Vol. 7 671 Ivyspring International Publisher Journal of Cancer 2016; 7(6): 671-680. doi: 10.7150/jca.13684 Research Paper Sex Difference of Egfr Expression and Molecular Pathway in the Liver: Impact on Drug Design and Cancer Treatments? Lishi Wang1,2, Jianqi Xiao1,3, Weikuan Gu1, Hong Chen3 1. Department of Orthopedic Surgery and BME-Campbell Clinic, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA. 2. Department of Basic Medical Research, Inner Mongolia Medical University, Inner Mongolia, 010110, China. 3. Center of integrative research, The first Hospital of Qiqihaer City, 30 Gongyuan Road, Longsha District, Qiqihaer, Heilongjiang, 161005, PR China. Corresponding authors: Weikuan Gu, 956 Court Ave, Memphis, TN 38163, USA. Tel: 1-901-448-2259; Email: [email protected]; Hong Chen, 30 Gongyuan Road, Longsha District, Qiqihaer, Heilongjiang, 161005, PR China. Tel: 86-0452-2425981; Email: [email protected]. © Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. See http://ivyspring.com/terms for terms and conditions. Received: 2015.08.28; Accepted: 2016.01.22; Published: 2016.03.20 Abstract Epidermal growth factor receptor (EGFR) has been used as the target in drug design for cancer treatment including the liver cancer. Men and women have different levels of EGFR expression during the life. The whole genome expression profiles of livers of recombinant inbred (RI) strains derived from C57BL/6J (B6) X DBA/2J (D2) were used to compare three major molecular aspects of Egfr gene: the relative expression levels, gene network and eQTLs that regulate the expression of Egfr between female and male mice. Our data suggest that there is a significant difference in the expression levels in the liver between female and male mice. Several important genes in the gene network of Egfr are differentially expressed between female and male mice. The regulatory elements for the expression levels of Egfr between female and male mice are also different. In summary, our data reveals an important sex difference in the Egfr pathways in the liver of the mice. These data may have substantial impact on drug development and dosage determinant for women and men in the clinical trials. Key words: Cancer, Egfr, liver, Mice, Pathway, Sex. Introduction Epidermal growth factor receptor (Egfr) is during life [5-6]. Mouse models have also suggest that involved in tissue development and in a variety of accelerates hepatocellular carcinoma progression in a cellular functions, such as cell proliferation, sex-dependent manner in a mouse model of differentiation, motility, and survival [1]. Most hepatocarcinogenesis [7-8]. These data indicated that importantly, it has a significant role in cancer gender difference may affect the cancer development, development [2]. It is highly expressed in liver and cancer treatment, and cancer survival. also regulated by estrogen [3]. Therefore, it is Several drugs for the treatment of important to understand its molecular pathways in hepatocarcinomas have been developed by targeting liver and similarities and differences between men the Egfr. For example, erlotinib, an epidermal growth and women. factor receptor and tyrosine kinase inhibitor, is a There are considerable reports on the role of Egfr targeted drug that was approved for the treatment of in the cancer development. Recently, Lanaya et al. [4] hepatocellular carcinomas [9]. Lapatinib is an reported that the presence of Egfr-positive liver inhibitor of both epidermal growth factor receptor macrophages in Hepatocellular carcinoma patients is and HER2/NEU, whereas both of which are associated with poor survival. Accompanied is the implicated in hepatocarcinogenesis [10]. While the fact that men and women have different levels of Egfr drugs based on anti Egfr are in development and in http://www.jcancer.org Journal of Cancer 2016, Vol. 7 672 clinical trials, its gender specificity should have been method reported previously [14]. R values were thoroughly investigated. In order to obtain compared between the association of female and male meaningful data, the study of sex-specific molecular mice. We followed the standard criteria for the strong, pathways needs samples of populations of both sexes correlation, and none correlation. When R value is of the same age, genomic background, and equal or more than 0.7 or -0.7, we regard the environment. It is extremely difficult to collect such a correlation as strong positive or negative. When R population from humans. Therefore, utilizations of value is between 0.35 and 0.69 or -0.35 and -0.69, the animal models have been as the alternative approach correlation exists but not strong. Any R values for the study of the gender difference of humans [11]. between 0 and 0.35 or 0 and -0.35 will be treated as The purpose of this work is to systematically none correlation [14]. The gene networks were investigate the sex differences of Egfr using high constructed using tools in the GeneNetwork. We quality data from the liver of a mouse population of constructed the gene network based on the Network recombinant inbred (RI) strains derived from Graph. Network graph is often used to visualize C57BL/6J (B6) X DBA/2J (D2) [12-13]. multiple sets of interactions. It consists of nodes and edge connecting nodes. In addition, the network Materials and Methods graph can represent the strength of the interaction by the thickness of the edge—that is, the higher the Data sets for analysis of gene expression number of interactions between the two nodes, the profiles thicker the edge becomes. UNC Agilent G4121A Liver Database (Jul04) was used for this analysis (http://www. Mapping transcriptomic loci (eQTL) that genenetwork.org/webqtl/main.py). The data set regulates the expression level of Egfr in female includes gene expression in livers of naive mice of and male mice both sexes from C57BL/6J, DBA/2J, B6D2F1, and 37 Transcriptome mapping with GeneNetwork was BXD strains using Agilent G4121A [12-13 ]. The data conducted to identify the chromosomal regions that sets at GeneNetwork are publically available and they affect the expression of Egfr in female and male mice. were validated using sex specific probe sets such as After we obtained the transcriptome maps, we Xist and Dby. In general, sex-balanced samples (one compared them to see whether there is a difference array from male cases, one array from female cases) between maps of female and male mice and among from RI strains derived from C57BL/6J (B6) X different tissues. We focused on the loci that have LRS DBA/2J (D2) and parental strains were used. While score equal to or higher than the significant levels. If they are collected at the similar age, performed with we did not find the loci at the significant levels, we the same microarray platform, and grown in the same then looked at the loci at the suggestive levels [14-15]. environment, most of them are from different RI For the loci showing sex difference, we strains. However, these RI strains are all derived from examined the candidate genes that regulate the Egfr the same two progenitors. Also, the gene expression expression level. We focused on the genes under the profiles of both female and male of two progenitors peak region of the eQTL, which usually is the are generated separately. Additional details regarding chromosome region with LRS scores at the significant animals, microarrays, data acquisition, processing, or suggestive levels [14]. and analyses can be found at WebQTL.org After we identified the genes in the chromosome (http://webqtl.org/dbdoc/LV_G_0106_B.html). region under the peak region of eQTL, we searched Collections of data on expression levels of Egfr the literature report to see whether any of these genes have been reported to regulate or functionally and associated genes associate with Egfr. We used the PGMapper to For the expression data of Egfr and its associated conduct such a search [16]. It is a software tool for genes we collected the expression data of Egfr axis automatically matching defined functional terms to from two sets of data, the male and the female sets. genes from a defined genome region by combining We used the Actin beta as controls for the Egfr. When the mapping information from the Ensembl database multiple probes were presented for the gene, the and gene function information from the OMIM and probe with the highest expression level was chosen PubMed databases. for the analysis while the others were used as reference. Additional Statistical Analysis The top 50 associated genes in each dataset on The association of the expression levels of Egfr the basis of Pearson correlation were used for plotting between female and male mouse populations Network Graphs in GeneNetwork. T–test was We conducted the association analysis using the http://www.jcancer.org Journal of Cancer 2016, Vol. 7 673 performed to test the levels of gene expression levels of different strains. We also conducted the same between the male and female mice. P value of 0.05 statistical analyses on the levels of Egfr expression was regarded as the largest value of indication of between the male and female mice. For Egfr, the P significant difference between the two populations. value for T test between the female and male is 1.07488E-17. The R value from the correlation analysis Results is 0.31. Therefore, there seems a difference in the expression levels between the male and female mice. Expression levels of Egfr between female and Thus, there is no difference in the expression level of male in the Liver Actin β between the female and male populations We conducted statistical analysis using data of while there is a significant sex difference in the Egfr gene expression of livers from a total of 39 strains, expression levels.
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